Publications by authors named "Thomas Carroll"

210 Publications

Argonaute-CLIP delineates versatile, functional RNAi networks in Aedes aegypti, a major vector of human viruses.

Cell Host Microbe 2021 Mar 29. Epub 2021 Mar 29.

Laboratory of Virology and Infectious Disease, the Rockefeller University, New York, NY 10065, USA. Electronic address:

Argonaute (AGO) proteins bind small RNAs to silence complementary RNA transcripts, and they are central to RNA interference (RNAi). RNAi is critical for regulation of gene expression and antiviral defense in Aedes aegypti mosquitoes, which transmit Zika, chikungunya, dengue, and yellow fever viruses. In mosquitoes, AGO1 mediates miRNA interactions, while AGO2 mediates siRNA interactions. We applied AGO-crosslinking immunoprecipitation (AGO-CLIP) for both AGO1 and AGO2, and we developed a universal software package for CLIP analysis (CLIPflexR), identifying 230 small RNAs and 5,447 small RNA targets that comprise a comprehensive RNAi network map in mosquitoes. RNAi network maps predicted expression levels of small RNA targets in specific tissues. Additionally, this resource identified unexpected, context-dependent AGO2 target preferences, including endogenous viral elements and 3'UTRs. Finally, contrary to current thinking, mosquito AGO2 repressed imperfect targets. These findings expand our understanding of small RNA networks and have broad implications for the study of antiviral RNAi.
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http://dx.doi.org/10.1016/j.chom.2021.03.004DOI Listing
March 2021

Impact of subspecialty training on management of laryngopharyngeal reflux: results of a worldwide survey.

Eur Arch Otorhinolaryngol 2021 Feb 27. Epub 2021 Feb 27.

Division of Laryngology and the Professional Voice Department of Otolaryngology, Communication Science Medical College of Wisconsin, Milwaukee, WI, USA.

Objective: To study the management of laryngopharyngeal reflux (LPR) among the subspecialties of practicing otolaryngology-head and neck surgeons and their trainees.

Methods: A survey was sent to over 8000 otolaryngologists (OTOHNS) over 65 countries, utilizing membership lists of participating otolaryngological societies. The outcomes were answers to questions regarding LPR knowledge and practice patterns, and included queries about its definition, prevalence, clinical presentation, diagnosis, and treatment.

Results: Of the 824 respondents, 658 practiced in one specific otolaryngologic subspecialty. The symptoms and findings thought to be the most related to LPR varied significantly between subspecialists. Extra-laryngeal findings were considered less by laryngologists while more experienced OTOHNS did not often consider digestive complaints. Compared with colleagues, otologists, rhinologists and laryngologists were less aware of the involvement of LPR in otological, rhinological and laryngological disorders, respectively. Irrespective of subspecialty, OTOHNS consider symptoms and signs and a positive response to empirical therapeutic trial to establish a LPR diagnosis. Awareness regarding the usefulness of impedance pH-studies is low in all groups. The therapeutic approach significantly varies between groups, although all were in agreement for the treatment duration. The management of non-responder patients demonstrated significant differences among laryngologists who performed additional examinations. The majority of participants (37.1%) admitted to being less than knowledgeable about LPR management.

Conclusions: LPR knowledge and management vary significantly across otolaryngology subspecialties. International guidelines on LPR management appear necessary to improve knowledge and management of LPR across all subspecialties of otolaryngology.
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http://dx.doi.org/10.1007/s00405-021-06710-yDOI Listing
February 2021

Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.

Cell Metab 2021 Mar 16;33(3):499-512.e6. Epub 2021 Feb 16.

Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY 10065, USA. Electronic address:

Obesity is a major risk factor for adverse outcomes in breast cancer; however, the underlying molecular mechanisms have not been elucidated. To investigate the role of crosstalk between mammary adipocytes and neoplastic cells in the tumor microenvironment (TME), we performed transcriptomic analysis of cancer cells and adjacent adipose tissue in a murine model of obesity-accelerated breast cancer and identified glycine amidinotransferase (Gatm) in adipocytes and Acsbg1 in cancer cells as required for obesity-driven tumor progression. Gatm is the rate-limiting enzyme in creatine biosynthesis, and deletion in adipocytes attenuated obesity-driven tumor growth. Similarly, genetic inhibition of creatine import into cancer cells reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals upregulated the fatty acyl-CoA synthetase Acsbg1 to promote creatine-dependent tumor progression. These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the TME necessary for obesity-driven breast cancer progression.
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http://dx.doi.org/10.1016/j.cmet.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954401PMC
March 2021

Hypertrophic Cardiomyopathy as an Unexpected Mimic of Inducible Laryngeal Obstruction: The Case for Cardiopulmonary Exercise Testing in Otolaryngology.

J Voice 2020 Dec 30. Epub 2020 Dec 30.

Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.

Introduction: Inducible laryngeal obstruction is a common and challenging cause of exertional dyspnea. We report a case of an unanticipated cardiac condition that presented with symptoms suggestive of inducible laryngeal obstruction.

Discussion: A 55-year-old man was evaluated for progressive exertional dyspnea and throat tightness, unexplained after multiple medical evaluations. Resting laryngeal examination was suspicious for laryngopharyngeal reflux and mild vocal fold adduction during quiet expiration. Given progressive and refractory symptoms, maximal cardiopulmonary exercise testing with intermittent laryngeal examination was performed. This study excluded laryngeal causes of exercise limitation and led to an unexpected diagnosis of persistent atrial flutter and hypertrophic cardiomyopathy.

Conclusion: Cardiopulmonary exercise testing with laryngeal examination can identify unexpected and life-threatening mimics of inducible laryngeal obstruction that may be missed by unmonitored exercise challenges. Suspicion for inducible laryngeal obstruction at rest may not predict the true nature of exercise limitation on cardiopulmonary exercise testing.
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http://dx.doi.org/10.1016/j.jvoice.2020.12.002DOI Listing
December 2020

Prevalence and clinical significance of esophageal motility disorders in patients with laryngopharyngeal reflux symptoms.

J Gastroenterol Hepatol 2020 Dec 29. Epub 2020 Dec 29.

Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background And Aim: Esophageal motor dysfunction may underlie impaired bolus/refluxate clearance in laryngopharyngeal reflux (LPR). However, the prevalence of esophageal dysmotility and its correlation with reflux parameters and symptoms in LPR is not well established. The aim of this study was to evaluate the prevalence of coexisting esophageal dysmotility among patients with suspected LPR.

Methods: This was a retrospective cohort study of 194 consecutive patients with LPR symptoms referred for high-resolution manometry (HRM) and combined hypopharyngeal-esophageal multichannel intraluminal impedance and pH testing at a tertiary center in March 2018 to August 2019. Validated symptom surveys were prospectively collected at time of testing, including Reflux Symptom Index, Gastroesophageal Reflux Disease Questionnaire, dominant symptom intensity, and 12-Item Short-Form Health Survey. HRM findings were categorized using Chicago Classification v3.0.

Results: Abnormal findings on HRM were identified in 84 (43.3%) patients, with ineffective esophageal motility (n = 60, 30.9%) as the most common diagnosis. A disorder of esophagogastric junction outflow or a major disorder of peristalsis was identified in 26 (13.4%) patients, including 2 (1%) with achalasia and 7 (3.6%) with jackhammer esophagus. Reflux burden (distal, proximal, or pharyngeal) on combined hypopharyngeal-esophageal multichannel intraluminal impedance and pH testing did not differ across HRM findings. Patients reporting esophageal symptoms were more likely to have a primary motility disorder (odds ratio 2.34, P = 0.04). However, no significant differences in Reflux Symptom Index, Gastroesophageal Reflux Disease Questionnaire, or 12-Item Short-Form Health Survey were noted across HRM diagnoses.

Conclusion: Esophageal motility disorders are prevalent among patients with LPR symptoms, including up to one in seven with esophagogastric junction outflow or major peristaltic disorder. Patients with abnormal motility more likely report esophageal symptoms. Clinicians should be aware of these coexisting conditions, particularly in those with refractory symptoms.
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http://dx.doi.org/10.1111/jgh.15391DOI Listing
December 2020

Laryngeal complications of COVID-19.

Laryngoscope Investig Otolaryngol 2020 Dec 30;5(6):1117-1124. Epub 2020 Oct 30.

Department of Otolaryngology-Head and Neck Surgery Massachusetts Eye and Ear Infirmary Boston Massachusetts USA.

Objective: To describe and visually depict laryngeal complications in patients recovering from coronavirus disease 2019 (COVID-19) infection along with associated patient characteristics.

Study Design: Prospective patient series.

Setting: Tertiary laryngology care centers.

Subjects And Methods: Twenty consecutive patients aged 18 years or older presenting with laryngological complaints following recent COVID-19 infection were included. Patient demographics, comorbid medical conditions, COVID-19 diagnosis dates, symptoms, intubation, and tracheostomy status, along with subsequent laryngological symptoms related to voice, airway, and swallowing were collected. Findings on laryngoscopy and stroboscopy were included, if performed.

Results: Of the 20 patients enrolled, 65% had been intubated for an average duration of 21.8 days and 69.2% requiring prone-position mechanical ventilation. Voice-related complaints were the most common presenting symptom, followed by those related to swallowing and breathing. All patients who underwent flexible laryngoscopy demonstrated laryngeal abnormalities, most frequently in the glottis (93.8%), and those who underwent stroboscopy had abnormalities in mucosal wave (87.5%), periodicity (75%), closure (50%), and symmetry (50%). Unilateral vocal fold immobility was the most common diagnosis (40%), along with posterior glottic (15%) and subglottic (10%) stenoses. 45% of patients underwent further procedural intervention in the operating room or office. Many findings were suggestive of intubation-related injury.

Conclusion: Prolonged intubation with prone-positioning commonly employed in COVID-19 respiratory failure can lead to significant laryngeal complications with associated difficulties in voice, airway, and swallowing. The high percentage of glottic injuries underscores the importance of stroboscopic examination. Otolaryngologists must be prepared to manage these complications in patients recovering from COVID-19.

Level Of Evidence: IV.
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http://dx.doi.org/10.1002/lio2.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752067PMC
December 2020

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Cell 2020 Dec 8;183(7):1826-1847.e31. Epub 2020 Dec 8.

St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY, USA. Electronic address:

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 γδ T lymphocytes, and of Mycobacterium-non reactive classic T1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 αβ T and non-classic CD4 αβ T1 lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 αβ T, and CD4 αβ T1 cells unable to compensate for this deficit.
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http://dx.doi.org/10.1016/j.cell.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770098PMC
December 2020

Management of Laryngopharyngeal Reflux Around the World: An International Study.

Laryngoscope 2021 May 17;131(5):E1589-E1597. Epub 2020 Nov 17.

Laryngopharyngeal Reflux Study Group of Young-Otolaryngologists of the International Federations of Oto-rhino-laryngological Societies (YO-IFOS), Paris, France.

Objective: To investigate worldwide practices of otolaryngologists in the management of laryngopharyngeal reflux (LPR).

Methods: An online survey was sent on the management of LPR to members of many otolaryngological societies. The following aspects were evaluated: LPR definition, prevalence, clinical presentation, diagnosis, and treatment.

Results: A total of 824 otolaryngologists participated, spread over 65 countries. The symptoms most usually attributed to LPR are cough after lying down/meal, throat clearing and globus sensation while LPR-related findings are arytenoid erythema and posterior commissure hypertrophy. Irrespective to geography, otolaryngologists indicate lack of familiarity with impedance pH monitoring, which they attribute to lack of knowledge in result interpretation. The most common therapeutic regimens significantly vary between world regions, with a higher use of H2 blocker in North America and a lower use of alginate in South America. The duration of treatment also significantly varies between different regions, with West Asia/Africa and East Asia/Oceania otolaryngologists prescribing medication for a shorter period than the others. Only 21.1% of respondents are aware about the existence of nonacid LPR. Overall, only 43.2% of otolaryngologists believe themselves sufficiently knowledgeable about LPR.

Conclusions: LPR knowledge and management significantly vary across the world. International guidelines on LPR definition, diagnosis, and treatment are needed to improve knowledge and management around the world.

Level Of Evidence: N.A. Laryngoscope, 131:E1589-E1597, 2021.
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http://dx.doi.org/10.1002/lary.29270DOI Listing
May 2021

BMP signaling: at the gate between activated melanocyte stem cells and differentiation.

Genes Dev 2020 Dec 12;34(23-24):1713-1734. Epub 2020 Nov 12.

Robin Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.

Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing converging signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated. Employing conditional lineage-specific genetic ablation studies in mice, we found that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream from activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1- and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.
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http://dx.doi.org/10.1101/gad.340281.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706702PMC
December 2020

Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function.

Nat Commun 2020 10 29;11(1):5469. Epub 2020 Oct 29.

Department of Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK.

Zbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability. Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches, here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of nuclear respiratory factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, downregulation of its target genes, and impaired complex I biogenesis. Our study establishes Zbtb11 as an essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and may help to understand the aetiology of Zbtb11-associated intellectual disability.
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http://dx.doi.org/10.1038/s41467-020-19205-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596099PMC
October 2020

Sensory Discrimination of Blood and Floral Nectar by Aedes aegypti Mosquitoes.

Neuron 2020 12 12;108(6):1163-1180.e12. Epub 2020 Oct 12.

Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY 10065, USA; Kavli Neural Systems Institute, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address:

Blood-feeding mosquitoes survive by feeding on nectar for metabolic energy but require a blood meal to develop eggs. Aedes aegypti females must accurately discriminate blood and nectar because each meal promotes mutually exclusive feeding programs with distinct sensory appendages, meal sizes, digestive tract targets, and metabolic fates. We investigated the syringe-like blood-feeding appendage, the stylet, and discovered that sexually dimorphic stylet neurons taste blood. Using pan-neuronal calcium imaging, we found that blood is detected by four functionally distinct stylet neuron classes, each tuned to specific blood components associated with diverse taste qualities. Stylet neurons are insensitive to nectar-specific sugars and respond to glucose only in the presence of additional blood components. The distinction between blood and nectar is therefore encoded in specialized neurons at the very first level of sensory detection in mosquitoes. This innate ability to recognize blood is the basis of vector-borne disease transmission to millions of people worldwide.
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http://dx.doi.org/10.1016/j.neuron.2020.09.019DOI Listing
December 2020

Failed Swallows on High-Resolution Manometry Independently Correlates With Severity of LPR Symptoms.

J Voice 2020 Sep 29. Epub 2020 Sep 29.

Divisions of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Abnormal esophageal motility is prevalent in gastroesophageal reflux disease patients; however, its relationship with laryngopharyngeal reflux (LPR) symptom severity remains unclear. Altered esophageal transit may contribute to LPR symptoms. We aimed to examine the relationship between reflux symptom index (RSI), a validated questionnaire for LPR symptoms, and abnormal esophageal motility on high-resolution manometry (HRM).

Methods: A total of 133 consecutive patients (55.9 ± 14.6 years, 69.9% female) with suspected LPR referred for HRM and multichannel intraluminal impedance-pH study (MII-pH) at a tertiary center from March 2015 to October 2017 were included. RSI questionnaire was prospectively collected prior to motility testing. Authors analyzing HRM and MII-pH were blinded to RSI findings. Statistical analyses were performed using Student's t test or Pearson's correlation (univariate) and general linear regression (multivariable).

Results: Mean RSI was higher among patients with ineffective esophageal motility than those with normal motility (23.7 vs 18.6, P = 0.01). Significant positive correlation was found between RSI and percent failed swallows (R = 0.21, P = 0.03), but not percent weak swallows. On multivariable analysis, percent ineffective (failed or weak) swallows was significantly associated with RSI (β-coefficient: 0.072, P = 0.05) after controlling for age, gender, BMI, smoking, prior PPI use, and reflux on MII-pH. When analyzed separately, percent failed swallows (β-coefficient: 0.095, P= 0.02), but not percent weak swallows, independently predicted higher RSI.

Conclusions: Ineffective swallows, particularly failed swallows, are independently associated with higher RSI in patients with suspected LPR, even after controlling for reflux on MII-pH. Esophageal dysmotility may play a role in suspected LPR symptoms independent of reflux. HRM should be routinely considered in evaluating these patients.
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http://dx.doi.org/10.1016/j.jvoice.2020.09.003DOI Listing
September 2020

Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene-expression programs in bladder cancer.

Proc Natl Acad Sci U S A 2020 10 28;117(41):25732-25741. Epub 2020 Sep 28.

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;

Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most-differentiated luminal tumors to the more aggressive and least-differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly cooccur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.
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http://dx.doi.org/10.1073/pnas.2008017117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568298PMC
October 2020

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Department of Dermatology and.

Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes, including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways; however, definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent. Here, we provide direct genetic evidence that dysregulation of the Hippo pathway in the Schwann cell lineage causes development of multiple schwannomas in mice. We found that canonical Hippo signaling through the effectors YAP/TAZ is required for schwannomagenesis and that MAPK signaling modifies schwannoma formation. Furthermore, cotargeting YAP/TAZ transcriptional activity and MAPK signaling demonstrated a synergistic therapeutic effect on schwannomas. Our new model provides a tractable platform to dissect the molecular mechanisms underpinning schwannoma formation and the role of combinatorial targeted therapy in schwannoma treatment.
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http://dx.doi.org/10.1172/jci.insight.141514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605536PMC
October 2020

Re-ACT: Remote Advanced Communication Training in a Time of Crisis.

J Pain Symptom Manage 2021 02 6;61(2):364-368. Epub 2020 Sep 6.

Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.

Background: We used a quality improvement framework to transform two-day and in-person advanced communication training (ACT) course into a remote ACT (Re-ACT) format to help clinicians improve serious illness conversation (SIC) skills.

Measures: We assessed the reach, impact, and costs of Re-ACT and compared these measures to in-person ACT courses.

Interventions: About 45-60 minutes of synchronous, remote sessions consisting of a didactic introduction to SIC skills, tailored to the SARS-Cov-2 (COVID-19) crisis, and a live demonstration of SICs with patient-actors.

Outcomes: The transition to Re-ACT sessions resulted in reaching a greater number of clinicians in less time, although depth of content and opportunities for skill practice decreased. Although both formats were well received, Re-ACT respondents felt less prepared than ACT respondents to use SIC skills. The costs of Re-ACT were significantly less than in-person ACT courses.

Conclusions/lessons Learned: We provided effective and well-received SIC training during a time of crisis. Future work should further define the optimal mix of in-person and remote experiences to teach SIC skills.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474842PMC
February 2021

National Trends in Daily Ambulatory Electronic Health Record Use by Otolaryngologists.

Laryngoscope 2021 May 2;131(5):975-981. Epub 2020 Sep 2.

Department of Surgery - Otolaryngology/Head & Neck Surgery, University of California, San Diego, San Diego, California, U.S.A.

Objective: Since their development in the 1970s electronic health records (EHRs) are now nearly ubiquitous. This study aims to characterize the daily interactions of otolaryngology providers with EHRs.

Methods: This study was a cross-sectional review of provider efficiency profile (PEP) data, as collected by a major EHR vendor. Participating institutions had 6 months of de-identified PEP data reviewed starting January 1, 2019. PEP data is generated for providers with scheduled patients, both attendings and advanced practice providers (APPs). Time metrics are recorded when a provider is interacting with the EHR including a 5-second time-out for inactivity.

Results: Data on 269 otolaryngologists and 29 APPs from 10 institutions were evaluated. On scheduled ambulatory clinic days attendings spent 70 ± 36 (mean ± standard deviation) min interacting in the EHR versus 108 ± 46 min for APPs. Of the daily EHR time, mean time in notes, clinical review, in basket, orders, and schedule were 30.1 ± 19.4, 9.6 ± 6.1, 7.3 ± 5.8, and 5.8 ± 7.6 min, respectively. Per patient visit, median (interquartile range) time in notes, clinical review, and orders were 3.19 (2.2-4.9), 1.14 (0.63-1.8), and 0.70 (0.47-1.05) min, respectively. Mean progress note length was 4638 ± 2143 characters.

Conclusion: Otolaryngology providers spend a meaningful portion of their clinic day interacting with the EHR. PEP data may provide means to target interventions and a metric to measure the impact of those interventions on provider EHR efficiency.

Level Of Evidence: 3 Laryngoscope, 131:975-981, 2021.
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http://dx.doi.org/10.1002/lary.29073DOI Listing
May 2021

Laryngeal Langerhans Cell Histiocytosis: A Case Report and Literature Review.

Ann Otol Rhinol Laryngol 2021 Apr 30;130(4):429-433. Epub 2020 Aug 30.

Harvard Medical School, Boston, MA, USA.

Objective: To describe a case of laryngeal Langerhans cell histiocytosis, discuss its characteristic features and management, and provide a review of the available literature.

Methods: A patient presenting to a tertiary care medical center with dyspnea and hoarseness is described. A literature review of laryngeal Langerhans cell histiocytosis cases was performed through a search of articles indexed in the National Institutes of Health PubMed system.

Results: We report a case of a 69-year old male, who presented with a laryngeal mass highly suspicious for laryngeal squamous cell carcinoma, was treated with laser excision, and was subsequently found to have laryngeal Langerhans cell histiocytosis upon histological analysis. Including our current case, we found six prior reported cases of laryngeal Langerhans cell histiocytosis in the literature. Of the six cases, four were in adults, while two were in children. Dyspnea is a common presenting complaint present in all cases. Smoking may be a potential risk factor.

Conclusions: Laryngeal Langerhans cell histiocytosis is a rare condition and an important consideration in the differential diagnosis of patients presenting with a laryngeal mass and symptoms of dyspnea or hoarseness. Biopsy and histopathological analysis are key to the diagnosis. Surgical excision and radiotherapy are successful treatments used in clinical practice.
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http://dx.doi.org/10.1177/0003489420954883DOI Listing
April 2021

m6A RNA methylation impacts fate choices during skin morphogenesis.

Elife 2020 08 26;9. Epub 2020 Aug 26.

Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.

N-methyladenosine is the most prominent RNA modification in mammals. Here, we study mouse skin embryogenesis to tackle m6A's functions and physiological importance. We first landscape the m6A modifications on skin epithelial progenitor mRNAs. Contrasting with in vivo ribosomal profiling, we unearth a correlation between m6A modification in coding sequences and enhanced translation, particularly of key morphogenetic signaling pathways. Tapping physiological relevance, we show that m6A loss profoundly alters these cues and perturbs cellular fate choices and tissue architecture in all skin lineages. By single-cell transcriptomics and bioinformatics, both signaling and canonical translation pathways show significant downregulation after m6A loss. Interestingly, however, many highly m6A-modified mRNAs are markedly upregulated upon m6A loss, and they encode RNA-methylation, RNA-processing and RNA-metabolism factors. Together, our findings suggest that m6A functions to enhance translation of key morphogenetic regulators, while also destabilizing sentinel mRNAs that are primed to activate rescue pathways when m6A levels drop.
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http://dx.doi.org/10.7554/eLife.56980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535931PMC
August 2020

COVID-19 After Effects: Concerns for Singers.

J Voice 2020 Aug 6. Epub 2020 Aug 6.

Janette Ogg Voice Research Center, Shenandoah Conservatory, Winchester, VA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jvoice.2020.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409791PMC
August 2020

Singing and the Pandemic: Return to Performance?

J Voice 2021 Mar 19;35(2):172-173. Epub 2020 Aug 19.

BWH Voice Program, Brigham and Women's Hospital, Boston, PA, USA; Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston, PA, USA.

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http://dx.doi.org/10.1016/j.jvoice.2020.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435334PMC
March 2021

MVP-Medical Situation, Values, and Plan: A Memorable and Useful Model for All Serious Illness Conversations.

J Pain Symptom Manage 2020 Nov 30;60(5):1059-1065. Epub 2020 Jul 30.

Division of Palliative Care, University of Rochester Medicine, Rochester, New York, USA.

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http://dx.doi.org/10.1016/j.jpainsymman.2020.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390732PMC
November 2020

Development and Validation of the Short Version of the Reflux Symptom Score: Reflux Symptom Score-12.

Otolaryngol Head Neck Surg 2021 01 21;164(1):166-174. Epub 2020 Jul 21.

Research Committee of the Young Otolaryngologists, International Federations of ORL Societies, Paris, France.

Objective: To develop and validate a short version of the Reflux Symptom Score-the 12-question Reflux Symptom Score-12 (RSS-12)-for patients with laryngopharyngeal reflux disease (LPR).

Study Design: Prospective study.

Setting: Multicenter academic hospitals.

Methods: Patients with LPR diagnosed via multichannel intraluminal impedance pH monitoring were enrolled from 3 European hospitals. Healthy individuals completed the study. Individuals completed the Reflux Symptom Score, Reflux Symptom Index (RSI), and Voice Handicap Index (VHI) at baseline and 3 months posttreatment. The Reflux Symptom Score was completed twice within a 7-day period to assess test-retest reliability. Cronbach's α was used for assessing internal consistency. The RSS-12 was developed and validity assessed through a comparison of the RSS-12, RSI, and VHI. Responsiveness to change was evaluated through the pre- to posttreatment evolution of the RSS-12 total score. Receiver operating characteristic analysis was used to determine the RSS-12 threshold that is suggestive of LPR.

Results: The RSS-12 was characterized by high test-retest reliability ( = 0.956) and adequate internal consistency reliability (α = 0.739). The RSS-12 was significantly correlated with the RSI ( = 0.845), suggesting high external validity. The RSS-12 total and item scores were significantly higher in patients with LPR as compared with healthy individuals ( = .001), supporting high internal validity. RSS-12, VHI, and RSI significantly improved throughout treatment. Regarding the receiver operating characteristic curve, an RSS-12 score >11 is suggestive of LPR, exhibiting a sensitivity of 94.5% and a specificity of 86.2%.

Conclusion: The RSS-12 is a shorter, reliable, and valid self-administered patient-reported outcome measure questionnaire that can be used in the outpatient setting to suggest and monitor LPR.
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http://dx.doi.org/10.1177/0194599820941003DOI Listing
January 2021

Identification and characterization of cellular heterogeneity within the developing renal interstitium.

Development 2020 08 14;147(15). Epub 2020 Aug 14.

Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

Kidney formation requires the coordinated growth of multiple cell types including the collecting ducts, nephrons, vasculature and interstitium. There is a long-held belief that interactions between progenitors of the collecting ducts and nephrons are primarily responsible for kidney development. However, over the last several years, it has become increasingly clear that multiple aspects of kidney development require signaling from the interstitium. How the interstitium orchestrates these various roles is poorly understood. Here, we show that during development the interstitium is a highly heterogeneous patterned population of cells that occupies distinct positions correlated to the adjacent parenchyma. Our analysis indicates that the heterogeneity is not a mere reflection of different stages in a linear developmental trajectory but instead represents several novel differentiated cell states. Further, we find that β-catenin has a cell autonomous role in the development of a medullary subset of the interstitium and that this non-autonomously affects the development of the adjacent epithelia. These findings suggest the intriguing possibility that the different interstitial subtypes may create microenvironments that play unique roles in development of the adjacent epithelia and endothelia.
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http://dx.doi.org/10.1242/dev.190108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438011PMC
August 2020

Involvement of Laryngopharyngeal Reflux in Select Nonfunctional Laryngeal Diseases: A Systematic Review.

Otolaryngol Head Neck Surg 2021 01 23;164(1):37-48. Epub 2020 Jun 23.

Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA.

Objectives: To investigate the existing published evidence supporting the role of laryngopharyngeal reflux (LPR) in the development of the select nonfunctional laryngeal diseases of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections.

Data Sources: PubMed, Cochrane Library, and Scopus.

Review Methods: A systematic review was performed by 3 independent investigators for studies providing information about the prevalence and role of LPR in the development of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. Diagnostic criteria and clinical outcome evaluation of included studies were analyzed with PRISMA criteria.

Results: Of the 64 relevant publications, 27 clinical and 4 basic science studies were included. Ten studies used objective reliable examinations for LPR diagnosis (eg, dual- or triple-probe or oropharyngeal pH monitoring, multichannel intraluminal impedance-pH monitoring, or pepsin detection). According to the bias analysis and the results of studies, the association between LPR and laryngotracheal stenosis, leukoplakia, laryngeal papillomatosis, or vocal fold granuloma remains poorly demonstrated. There is a notable heterogeneity among included studies regarding their inclusion criteria, diagnostic methods, and clinical outcome evaluation. Although some experimental findings support the involvement of bile salts and other gastroduodenal proteins active in alkaline pH, no included clinical studies assessed the role of nonacid and mixed reflux through multichannel intraluminal impedance-pH monitoring.

Conclusion: The involvement of LPR in the development of leukoplakia, laryngotracheal stenosis, vocal fold granuloma, and laryngeal papillomatosis is currently not demonstrated. The potential relationship between LPR and these select nonfunctional laryngeal diseases must be confirmed through future clinical and experimental studies considering acid, nonacid, and mixed LPR.
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http://dx.doi.org/10.1177/0194599820933209DOI Listing
January 2021

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics.

Proc Natl Acad Sci U S A 2020 06 16;117(26):15085-15095. Epub 2020 Jun 16.

Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065;

Comparative transcriptomics between differentiating human pluripotent stem cells (hPSCs) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate human pluripotent stem cell-derived Purkinje cells (hPSC-PCs) that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we used TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenic - TRAP hPSC line to profile gene expression in differentiating hPSC-PCs, finding that the key gene expression pathways of differentiated hPSC-PCs most closely matched those of late juvenile mouse PCs (P21). Comparative bioinformatics identified classical PC gene signatures as well as novel mitochondrial and autophagy gene pathways during the differentiation of both mouse and human PCs. In addition, we identified genes expressed in hPSC-PCs but not mouse PCs and confirmed protein expression of a novel human PC gene, CD40LG, expressed in both hPSC-PCs and native human cerebellar tissue. This study therefore provides a direct comparison of hPSC-PC and mouse PC gene expression and a robust method for generating differentiated hPSC-PCs with human-specific gene expression for modeling developmental and degenerative cerebellar disorders.
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http://dx.doi.org/10.1073/pnas.2000102117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334519PMC
June 2020

Stromal β-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor.

Development 2020 07 31;147(21). Epub 2020 Jul 31.

Department of Molecular Biology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

Wilms' tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial and stromal components, suggesting tumors arise from the dysregulation of normal development. β-Catenin activation is observed in a significant proportion of WTs; however, much remains to be understood about how it contributes to tumorigenesis. Although activating β-catenin mutations are observed in both blastema and stromal components of WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of β-catenin in the nephrogenic lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of β-catenin in the stromal lineage non-autonomously prevents the differentiation of NPCs. Comparisons of the transcriptomes of kidneys expressing an activated allele of β-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal β-catenin activation results in histological and molecular features of human WT, providing insights into how alterations in the stromal microenvironment may play an active role in tumorigenesis.
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http://dx.doi.org/10.1242/dev.189597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406317PMC
July 2020

Independence of HIF1a and androgen signaling pathways in prostate cancer.

BMC Cancer 2020 May 25;20(1):469. Epub 2020 May 25.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK.

Background: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated.

Methods: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq.

Results: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic.

Conclusions: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.
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http://dx.doi.org/10.1186/s12885-020-06890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249645PMC
May 2020

Asynchronous mixing of kidney progenitor cells potentiates nephrogenesis in organoids.

Commun Biol 2020 May 11;3(1):231. Epub 2020 May 11.

The Rogosin Institute, New York, NY, USA.

A fundamental challenge in emulating kidney tissue formation through directed differentiation of human pluripotent stem cells is that kidney development is iterative, and to reproduce the asynchronous mix of differentiation states found in the fetal kidney we combined cells differentiated at different times in the same organoid. Asynchronous mixing promoted nephrogenesis, and heterochronic organoids were well vascularized when engrafted under the kidney capsule. Micro-CT and injection of a circulating vascular marker demonstrated that engrafted kidney tissue was connected to the systemic circulation by 2 weeks after engraftment. Proximal tubule glucose uptake was confirmed, but despite these promising measures of graft function, overgrowth of stromal cells prevented long-term study. We propose that this is a technical feature of the engraftment procedure rather than a specific shortcoming of the directed differentiation because kidney organoids derived from primary cells and whole embryonic kidneys develop similar stromal overgrowth when engrafted under the kidney capsule.
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http://dx.doi.org/10.1038/s42003-020-0948-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214420PMC
May 2020

Time Dependence of Few-Body Förster Interactions among Ultracold Rydberg Atoms.

Phys Rev Lett 2020 Apr;124(13):133402

Department of Physics, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, USA.

Rubidium Rydberg atoms in either |m_{j}| sublevel of the 36p_{3/2} state can exchange energy via Stark-tuned Förster resonances, including two-, three-, and four-body dipole-dipole interactions. Three-body interactions of this type were first reported and categorized by Faoro et al. [Nat. Commun. 6, 8173 (2015)NCAOBW2041-172310.1038/ncomms9173] and their Borromean nature was confirmed by Tretyakov et al. [Phys. Rev. Lett. 119, 173402 (2017)PRLTAO0031-900710.1103/PhysRevLett.119.173402]. We report the time dependence of the N-body Förster resonance N×36p_{3/2,|m_{j}|=1/2}→36s_{1/2}+37s_{1/2}+(N-2)×36p_{3/2,|m_{j}|=3/2}, for N=2, 3, and 4, by measuring the fraction of initially excited atoms that end up in the 37s_{1/2} state as a function of time. The essential features of these interactions are captured in an analytical model that includes only the many-body matrix elements and neighboring atom distribution. A more sophisticated simulation reveals the importance of beyond-nearest-neighbor interactions and of always-resonant interactions.
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http://dx.doi.org/10.1103/PhysRevLett.124.133402DOI Listing
April 2020